1. Field of the Invention
The present invention relates to reconstituted surfactants which are useful for the treatment or prophylaxis of RDS and other respiratory disorders. The present invention also relates to methods of preparing such a reconstituted surfactant and pharmaceutical compositions which contain such a reconstituted surfactant. The present invention further relates to methods for the treatment or prophylaxis of RDS and other respiratory disorders by administering such a reconstituted surfactant.
2. Discussion of the Background
The human lung is composed of a large number of small air sacs, called alveoli, in which gases are exchanged between the blood and the air spaces of the lungs. In healthy individuals, this exchange is mediated by the presence of a protein-containing surfactant complex that prevents the lungs from collapsing at the end of expiration.
Lung surfactant complex is composed primarily of lipid and contains minor amounts of various proteins. An absence of adequate levels of this complex results in malfunction of the lung. This syndrome is called Respiratory Distress Syndrome (RDS) and it commonly affects preterm infants.
Said syndrome is effectively treated with modified natural surfactant preparations extracted from animal lungs. Commercially available modified surfactant preparations are, for example, Curosurf, derived from porcine lung, Infasurf, extracted form calf lung lavage, and Survanta, a chemically modified natural bovine lung extract.
The main constituents of these surfactant preparations are phospholipids, such as 1,2-dipalmitoyl-sn-glycero-3-phosphocholine commonly known as dipalmitoylphosphatidylcholine (DPPC), phosphatidylglycerol (PG), and surfactant hydrophobic proteins B and C (SP-B and SP-C).
Due to the drawbacks of the surfactant preparations from animal tissues, such as the complication of the production and sterilization processes and possible induction of immune reactions, synthetic surfactants mimicking the composition of the modified natural surfactants have been developed. Said synthetic surfactants are known as reconstituted surfactants. However the development of clinically active reconstituted surfactants has turned out to be complicated since the native hydrophobic proteins are too big to synthesize, structurally complex, and unstable in pure form.
In order to replace said native hydrophobic proteins, some synthetic polypeptides partially corresponding to their sequences and analogs thereof have been proposed in the prior art and are disclosed in for example WO 89/06657, WO 92/22315, WO 98/49191, WO 95/32992, U.S. Pat. No. 6,660,833, EP 413,957, and WO 91/18015.
WO 00/47623 disclosed synthetic polypeptides which are analogs of the native protein SP-C wherein: i) cysteine residues in position 5 and 6 have been replaced by Ser residues; ii) the Val residues of the ‘center region’ of SP-C have been substituted with other neutral and hydrophobic residues selected from the group consisting of Leu, Ile, and norleucine (nL); iii) some of the neutral amino acids present in the ‘center region’ of SP-C have been replaced with bulky or polar residues selected from the group consisting of Lys, Trp, Phe, Tyr, and Ornithine. Said artificial polypeptides are characterized by the fact that they are capable of folding like the native protein SP-C and, hence, interacting properly with the surfactant lipids and, thus, do not give rise to self-oligomerization.
WO 00/76535 generically discloses pulmonary surfactant preparations comprising at least one modification of the SP-B in combination with at least one modification of the SP-C protein.
In A. J. Waring, et al., (abstract presented at the Paediatric Academy Society Annual meeting held in San Francisco on Apr. 29-May 2, 2006) a study was undertaken to examine the activity of a synthetic surfactant constituted of the SP-C-mimic, SP-Cff, that is a synthetic 34-residue SP-C with phenylalanine instead of cysteine in positions 4 and 5, and the SP-B-mimic, Mini-B.
However, according to the available literature, in animal studies, the treatment with reconstituted surfactants gives rise to poor lung gas volumes and grade of alveolar patency at the end of expiration, and a ventilation is required with a positive end expiratory pressure (PEEP) in order to achieve an in vivo activity comparable to that achieved with modified natural surfactants (see, J. Johansson, et al., J. Appl. Physiol., 2003, 95, 2055-2063; and A. J. Davis, et al., Am. J. Respir. Crit. Care Med., 1998; 157, 553-559). Thus, the available reconstituted surfactant preparations are indeed not capable of forming a stable phospholipidic film in the alveoli at the end of expiration.
Moreover, all of the aforementioned documents are silent about the problem of the alveolar patency at the end of expiration and the effect of the disclosed preparations thereof.
Thus, there remains a need for a reconstituted surfactant with improved properties in terms of lung compliance.